Background Dual inhibition of PI3K and MAPK signaling is conceptually a promising anticancer therapy. Objective This phase 1b trial investigated the safety, maximum tolerated dose (MTD), recommended phase II dose, pharmacokinetics, tumor response, fuorodeoxyglucose positron emission tomography (FDG-PET) pharmacodynamics, and biomarker explorations for the combination of pan-PI3K inhibitor copanlisib and allosteric MEK inhibitor refametinib in patients with advanced solid tumors. Patients and methods This was an adaptive trial with eight dose cohorts combining dose escalation and varying schedules in repeated 28-day cycles. Patients received copanlisib (0.2–0.8 mg/kg intravenously) intermittently (days 1, 8, 15) or weekly (days 1, 8, 15, 22) each cycle, and refametinib (30–50 mg twice daily orally) continuously or 4 days on/3 days of. Patients with KRAS, NRAS, BRAF, or PI3KCA mutations were eligible for the expansion cohort. Results In the dose-escalation (n=49) and expansion (n=15) cohorts, the most common treatment-emergent adverse events included diarrhea (59.4%), nausea, acneiform rash, and fatigue (51.6% each). Dose-limiting toxicities included oral mucositis (n=4), increased alanine aminotransferase/aspartate aminotransferase (n=3), acneiform rash, hypertension (n=2 each), and diarrhea (n=1). MTD was copanlisib 0.4 mg/kg weekly and refametinib 30 mg twice daily. No pharmacokinetic interactions were identifed. Decreased tumor FDG uptake and MEK-ERK signaling inhibition were demonstrated during treatment. Best response was stable disease (n=21); median treatment duration was 6 weeks. Conclusions Despite sound rationale and demonstrable pharmacodynamic tumor activity in relevant tumor populations, a dose and schedule could not be identifed for this drug combination that were both tolerable and ofered clear efcacy in the population assessed.

Additional Metadata
Persistent URL dx.doi.org/10.1007/s11523-020-00714-0, hdl.handle.net/1765/128542
Journal Targeted Oncology
Citation
Ramanathan, R.K., Von Hoff, D.D, Eskens, F.A.L.M, Blumenschein, G., Richards, D., Genvresse, I., … Mross, K. (2020). Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer. Targeted Oncology, 15(2), 163–174. doi:10.1007/s11523-020-00714-0